The HIV capsid (CA) protein appears to be essential to particle assembly, incorporation of HIV pol gene products into particles, and formation of the mature virus core. The investigators will use biophysical, biochemical and genetic methods to examine structural interactions of HIV core proteins, to test structural predictions, and to develop in vitro oligomerization protocols for the assay of potential peptide-based methods for interference of Gag function. Sp. Aim 1. Electron diffraction-image analysis of the HIV core proteins: Purified histidine-tagged (his- tagged) HIV CA and Gag protein derivatives will be used to make two dimensional protein arrays on phosphatidyl choline (PC) monolayers containing novel nickel-chelating lipids. Stained protein arrays will be viewed by transmission electron microscopy (EM) to obtain data concerning capsid-capsid interactions. Unstained samples will be analyzed to obtain 5-10 angstrom resolution maps by image enhancement- electron diffraction methods. Sp. Aim 2. Examination of Gag interactions in vitro: Gag-Gag protein association will be assayed in vitro to determine optimal oligomerization conditions, and potential capsid-derived peptide inhibitors of assembly will be tested in the in vitro system. Epitope library screens also will be employed for identification of peptides which bind CA and may serve as candidate peptide inhibitors of core protein functions. Sp. Aim 3. Genetic and biochemical analysis of HIV virions: Genetic interactions of the capsid domain will be investigated via complementation analysis, and by assay for dominant-negative phenotypes to locate potential sites for antiviral interference. Putative capsid-binding peptides, identified in in vitro studies, will be tested for assembly into virus particles and inhibition of viral replication, and models of Gag protein interactions in virus particles will be evaluated.